Chasing the cancer demon.

Boveri's idea that somatic mutations are at the root of cancer found its first specific support with the investigation of leukemia and Burkitt's lymphoma, and the discovery of the mechanism of oncogene activation by balanced translocation. The study of retinoblastoma later led to the cloning of the first antioncogene, or tumor suppressor gene, and to understanding the mechanisms by which the wild-type genes lose activity. Only a small subset of cancer involves simple mechanisms. A category of hereditary disorders called the phakomatoses provide a perspective on the chain of oncogenic events in such cancers because of two-hit precursor lesions that have a low probability of malignant transformation. The common carcinomas are much more complex and are typically genetically unstable, owing either to mutational instability or chromosomal instability.